Anti‐inflammatory effects of cannabidiol against lipopolysaccharides in cardiac sodium channels

Background Sepsis, caused by a dysregulated response to infections, can lead to cardiac arrhythmias. However, the mechanisms underlying sepsis-induced inflammation, and how inflammation provokes cardiac arrhythmias, are not well understood. We hypothesized that cannabidiol (CBD) may ameliorate lipopolysaccharide (LPS)-induced cardiotoxicity, via Toll-like receptors (TLR4) and cardiac sodium channels (Na(V)1.5). Methods and results We incubated human immune cells (THP-1 macrophages) with LPS for 24 h, then extracted the THP-1 incubation media. ELISA assays showed that LPS (1 or 5 mu g center dot ml(-1)), in a concentration-dependent manner, or MPLA (TLR4 agonist, 5 mu g center dot ml(-1)) stimulated the THP-1 cells to release inflammatory cytokines (TNF-alpha and IL-6). Prior incubation (4 h) with CBD (5 mu M) or C34 (TLR4 antagonist: 5 mu g center dot ml(-1)) inhibited LPS and MPLA-induced release of both IL-6 and TNF-alpha. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were subsequently incubated for 24 h in the media extracted from THP-1 cells incubated with LPS, MPLA alone, or in combination with CBD or C34. Voltage-clamp experiments showed a right shift in the voltage dependence of Na(V)1.5 activation, steady state fast inactivation (SSFI), increased persistent current and prolonged in silico action potential duration in hiSPC-CMs incubated in the LPS or MPLA-THP-1 media. Co-incubation with CBD or C34 rescued the biophysical dysfunction caused by LPS and MPLA. Conclusion Our results suggest that CBD may protect against sepsis-induced inflammation and subsequent arrhythmias through (i) inhibition of the release of inflammatory cytokines, antioxidant and anti-apoptotic effects and/or (ii) a direct effect on Na(V)1.5.